Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.

By Simon N. Willis, Lin Chen, G. Dewson, A. Wei, Edwina Naik, J. Fletcher, Jerry M. Adams, D. Huang. Genes & Development, 2005

1,362 citations recorded by the source corpus.

Commitment of cells to apoptosis is governed largely by the interaction between members of the Bcl-2 protein family. Its three subfamilies have distinct roles: The BH3-only proteins trigger apoptosis by binding via their BH3 domain to prosurvival relatives, while the proapoptotic Bax and Bak have an essential downstream role involving permeabilization of organellar membranes and induction of caspase activation. We have investigated the regulation of Bak and find that, in healthy cells, Bak associates with Mcl-1 and Bcl-x(L) but surprisingly not Bcl-2, Bcl-w, or A1. These interactions require the Bak BH3 domain, which is also necessary for Bak dimerization and killing activity. When cytotoxic signals activate BH3-only proteins that can engage both Mcl-1 and Bcl-x(L) (such as Noxa plus Bad), Bak is displaced and induces cell death. Accordingly, the BH3-only protein Noxa could bind to Mcl-1, displace Bak, and promote Mcl-1 degradation, but Bak-mediated cell death also required neutralization of Bcl-x(L) by other BH3-only proteins. The results indicate that Bak is held in check solely by Mcl-1 and Bcl-x(L) and induces apoptosis only if freed from both. The finding that different prosurvival proteins have selective roles has notable implications for the design of anti-cancer drugs that target the Bcl-2 family.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/da892349d6249a4ed74d1c09e4b9ae6dfce26dd7

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Citations in the corpus

The Bcl-2 apoptotic switch in cancer development and therapy (2007, background): “The indirect activation model (Figure 3b), on the other hand, suggests that all the BH3-only proteins engage only their pro-survival relatives and act by preventing them from countering Bax or Bak activation (Chen et al., 2005; Willis et al., 2005; Willis et al., 2007).”
Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies (2006, background): “BAK and BAX are not kept in check by BCL-2, BCL-XL or MCL-1 In addition to VDAC2, BCL-X L and MCL-1 have been reported to keep BAK in chec”
Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. (2006, background): “In this model, the link between neutralization of antiapoptotic proteins and MOMP remains obscure (Chen et al., 2005; Willis et al., 2005).”
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. (2006, background): “Alternatively, mitochondrially localized BAK may play a principal role in sensitivity to ABT-737: BAK binds BCL-XL and MCL-1 and can assume a BH3-exposed, active conformation in healthy cells, which is kept incheck by MCL-1/BCL-XL (Willis et al., 2005).”
BCL-2 family antagonists for cancer therapy (2008, background): “BCL-X L and MCL1 seem to be the key direct antagonists of BA”
Diagnosing and exploiting cancer's addiction to blocks in apoptosis (2008, background): “An alternative, 'indirect' model holds that direct activation of BAX and BAK does not take plac”
Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis (2007, background): “1d ), which are resistant to apoptosis induced by a wide variety of death stimul”